Cancer, also known as a malignant tumor or malignant neoplasm, is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. In particular, hepatocellular carcinoma (HCC) is a fatal liver cancer affecting 600,000 people worldwide annually, and it ranks third in terms of global cancer mortality. The development and progression of HCC is largely associated with endemic hepatitis B or hepatitis C virus infection, alcoholic hepatitis, non-alcoholic steatohepatitis, hemochromatosis, obesity and consumption of aflatoxin B1. Surgical therapies including liver resection, liver transplantation as well as non-surgical therapies such as embolization, systemic chemotherapy and radiation therapy are currently available for the treatment/prognosis of HCC.
Signal Transducer and Activator of Transcription 3 (STAT3) is an inducible transcription factor/protein present in the cytoplasm of most cell types, and it is involved in extracellular signal transduction to the nucleus by cytokines of the IL-6 family, epidermal and platelet-derived growth factors. Thus, STAT3 governs differentiation, proliferation and survival of cells. Further, in a tumor, STAT3 is involved in its proliferation, development, survival, angiogenesis, metastasis and evasion. Activation of STAT3 is also known to transmit various survival signals by promoting the expression of genes involved in cell cycle progression (cyclin D1), angiogenesis (VEGF, HIF-1α), cell migration (MMP-2/9), immune evasion (RANTES) and anti-apoptotic genes (Bcl2, Bcl-xL, survivin). JAK1, JAK2, JAK3 and Tyrosine kinase 2 (TYK2) are the upstream kinases which phosphorylate different STAT proteins involved in different functions. Structurally, the activation of Janus kinase (JAK) and c-Src kinase leads to the phosphorylation of tyrosine 705 and homodimerization of STAT3, followed by its nuclear translocation to transcribe the target genes. Constitutive activation of STAT3 is observed in more than 15 types of solid and haematological tumors, including hepatocellular carcinoma, leukemia, lymphoma, prostate cancer, breast cancer, ovarian cancer and multiple myeloma. To summarize, STAT3 plays a critical role in progression of cancer (such as hepatocellular carcinoma).
Many compounds have been studied extensively for modulation of cancer-associated biological pathways and are shown to have anti-cancer activity in various tumor models. However, the compounds of prior art possess numerous drawbacks such as complex synthesis procedures, toxicity to normal cells, lack of stability, lack of improved/desired anti-cancer efficacy, and so on.
Thus, there is a necessity to develop better and efficient compounds/therapies for managing cancer. The present disclosure aims at providing such compounds which possess significantly improved anti-cancer activity.